Citicoline is a compound represented by formula (I). ##STR1## Citicoline is amorphous, hygroscopic powder, which has therapeutic utility, for example, as a cerebroprotectant, or a neuroprotectant. In particular, citicoline is beneficial the victims of ischemic stroke, head trauma, and, possibly, neurodegenerative disease. In addition, citicoline is used to treat unconsciousness resulting from cranial trauma, hemorrhages, cerebral thrombosis, and cerebropathies due to atherosclerosis (Secades J J. CDP-choline: pharmacological and clinical review. Methods Find Exp Clin Pharmacol 1995 Oct; 17 Suppl B:2-54).
For pharmaceutical applications, citicoline has been formulated in solution, suitable for parenteral administration, usually intravenous administration. However, currently available solid forms of citicoline suffer from a number of drawbacks. Commercially available forms of citicoline (or its salt, typically citicoline sodium) range in water content to not more than 5% by weight (relative to the citicoline), as determined by water loss on drying or by Karl Fischer moisture analysis. Normally, the amount of water present in commercially available forms of citicoline sodium ranges between 2% to 4% by weight. Such conventional solid forms of citicoline are unstable on exposure to atmospheric humidity. This instability, due to the hygroscopic nature of the molecule, is carried over to solid dosage formulations, such as tablets, capsules and the like, which contain conventional citicoline.
Because of its susceptibility to moisture and stated product specifications relating to water content, citicoline must be processed under special conditions, including a low humidity environment, to provide and maintain a relatively low water content. Manufacturers of pharmaceutical drug products must be able to show that their final dosage forms are stable and remain within certain stated specifications, including water content, hardness and physical integrity. To protect the compound against moisture during normal storage conditions special packaging materials must be used, including aluminum foil pouches or double-walled polyethylene bags equipped with desiccants. For example, U.S. Pat. No. 4,861,591 discloses a hard gelatin capsule consisting essentially of several moisture impervious outer layers of humidity-resistant excipients encapsulating the hygroscopic active ingredient.
Indeed, during formulation, citicoline sodium must be coated with excipients, such as castor oil and talc, to help retard the sorption of moisture. Despite that the tablets ultimately sorb water, swell and crack, limiting the shelf life of the product. Hence, much, if not all, effort in the art has been directed to insulating citicoline, its salts and its pharmaceutical dosage forms against unwanted exposure to atmospheric humidity. Various other methods are employed in the prior art to obtain stable forms of hygroscopic or deliquescent pharmaceuticals like citicoline.
U.S. Pat. No. 5,688,510 issued to Nakamichi et al., discloses processing en block by means of multi-screw extruder wherein a physiologically inert powdery additive and a macromolecular additive are added to the unstable active ingredient. While this process is claimed to be applicable to citicoline it is unrelated to the instant invention since it is based on totally different physical and chemical principles.
U.S. Pat. No. 5,811,547 issued to the same group of inventors, Nakamichi et al., discloses yet another method of obtaining stable pharmaceuticals by means of inducing a transition in crystalline state whereby a drug of interest passes through two separate zones maintained at different temperatures. Again, the disclosed process has nothing in common with the instant invention, either by principle or by design.
U.S. Pat. No. 3,687,932, issued to Nakamachi et al., discloses crystalline CDP-choline monohydrate that is allegedly stable when the water content in the formulation is around 5-6%. This disclosure, however, fails to demonstrate or suggest that stable crystalline forms of citicoline with higher hydration levels might exist. Indeed, all currently manufactured forms of citicoline contain no more than 5% of water by weight. Thus, the prevailing consensus dominating the prior art is that higher levels of water would render citicoline unstable and unusable for manufacturing pharmaceutical formulations.
Accordingly, it would be a significant advancement in the art to provide a novel form of citicoline, along with its solid tablet, capsule and like solid forms, having improved stability, structural integrity and other physicochemical, manufacturing, or pharmacological benefits over currently available forms. More particularly, it would advance the art to provide a solid form of citicoline that does not suffer detrimental consequences from exposure to atmospheric moisture and whose solid dosage forms exhibit improved physical storage stability. Similarly, it would be a welcome contribution and advancement to provide processes or methods for preparing such stable crystalline forms of citicoline, along with storage stable capsules, tablets, gelcaps and the like containing citicoline.
Such a "stabilized" form of citicoline is discovered by the present inventor. In particular, a hyperhydrated form of citicoline is provided by the instant invention, which substantially eliminates the shortcomings of conventional citicoline and its conventional formulations. Hence, the poor or problematic storage characteristics of pharmaceutical dosage forms of conventional citicoline, at least, are substantially eliminated by the present invention. While not wishing to be bound by theory, it is understood that the newly discovered hyperhydrated form of citicoline is essentially citicoline tetrahydrate. A pharmaceutical composition may, however, contain small amounts of lesser or higher hydrated forms of citicoline, e.g., monohydrate, dihydrate, trihydrate, etc. However, due to the high moisture content these forms are unlikely to be encountered. It is also understood that citicoline tetrahydrate is a hyperhydrated form of citicoline, and these two terms are used hereinafter interchangeably. The advantages that are offered by this new form of citicoline, as well as processes for making this hyperhydrated citicoline, are described in greater detail, below. It is important to note that the "stabilized" formulations of the present invention can be prepared by using the hyperhydrated form of citicoline, as an initial ingredient or starting material, or by incorporating an adequate amount of total water into the dosage form to ensure the in situ formation of the citicoline hyperhydrate from the conventionally obtained citicoline, as starting material for the desired formulation.